Bone mineral density (BMD) is a term that is commonly recognized as relating to the amount of calcified matter present per square centimeter of bone. It is understood that the term does not refer to a true density (as in mass per volume of material) but rather is used to communicate information about the strength of the bone and the susceptibility of the bone to fracture. Typically, BMD is evaluated using methods, such as Dual Energy X-ray Absorptiometry (or DEXA scan), ultrasound, and Quantitative Computed Tomography (QCT). Of the foregoing, DEXA scan often is considered to be the most reliable evaluation of BMD. For example, ultrasound is generally limited to evaluation of the calcaneus bone and is not useful for directly measuring sites common to osteoporotic fracture, such as the hip and spine. QCT typically is used with the spine and must be done following strict protocols in laboratories to provide acceptable reproducibility. Further test methods for evaluating BMD include single photon absorptiometry (SPA), dual photon absorptiometry (DPA), digital X-ray radiogammetry (DXR), and single energy X-ray absorptiometry (SEXA).
BMD is a highly important physical characteristic since it can be a direct indicator of susceptibility to fracture. In most adult populations, BMD peaks around the age of 30-35 and tends to slowly decline thereafter. The reduction in BMD arises from a decline in new bone cell production such that the resorption of existing bone cells by the body exceeds the rate of new bone cell production. FIG. 1 (which is available online at http://courses.washington.edu/bonephys/opbmd.html) illustrates the typical decline in BMD (shown in mg/cm2) for adults and shows how the decline can vary based upon both race and gender. Menopause in women is a highly significant event in relation to BMD as the decrease in BMD sharply accelerates for a period of time after menopause. Thus, post-menopausal women typically are encouraged to have BMD testing regularly to assess if treatment is required and what type of treatment should be pursued. The National Osteoporosis Foundation recommends BMD testing for the following individuals: all women aged 65 and older regardless of risk factors; younger postmenopausal women with one or more risk factors; postmenopausal women who present with fractures (to confirm the diagnosis and determine disease severity); estrogen deficient women at clinical risk for osteoporosis; individuals with vertebral abnormalities; individuals receiving, or planning to receive, long-term glucocorticoid (steroid) therapy; individuals with primary hyperparathyroidism; individuals being monitored to assess the response or efficacy of an approved osteoporosis drug therapy; and individuals with a history of eating disorders.
Reduced BMD commonly is recognized in relation to the conditions of osteopenia and osteoporosis, and the existence of these conditions is defined upon a patient's score from a BMD test, particularly the T-score from a DEXA scan. The T-score from a DEXA scan is a normalized value that indicates how a patient's BMD compares to the average of a young adult at peak BMD. The normalized value is expressed in standard deviations from the average. Thus, a T-score of 0 indicates no difference in BMD compared to the average young adult, a negative T-score indicates BMD below the average, and a positive T-score indicates BMD above the average. T-score is a normalized value because the average value varies depending upon race and gender. T-score also can vary from one bone to another in the same individual. Generally, a bone with a T-score of greater than −1 is considered to be within the normal range (although the negative score still indicates BMD below the normalized average). The condition of osteopenia typically is considered to exist for bone with a T-score of −1 to −2.5. The condition of osteoporosis typically is considered to exist for bone with a T-score of less than −2.5.
BMD can be correlated to bone strength and thus can be a predictor of risk for bone fracture. In general, the risk for bone fracture is expected to increase with every standard deviation below normal. In the elderly, bone fracture (particularly hip or vertebral fractures) can be correlated to increased mortality. Thus, improving BMD can be a goal of medical intervention in osteopenic and/or osteoporotic patients since BMD can be correlated to increased risk for fracture. While several interventions have been tried, there still remains a need in the art for treatments that can effectively increase BMD.
Treatment and prophylaxis of bone degeneration (i.e., loss of BMD) can take on many faces. Prevention typically starts in childhood with exercise and proper nutrition that includes sufficient calcium and vitamin D as both exercise and nutrition have been shown to be necessary for maximum BMD development. This is important because decrease in BMD with age has been shown to be slower when actual BMD at the peak age is greater.
When conditions of osteopenia and osteoporosis are present, many different therapies are available. Estrogen treatment of postmenopausal women may slow onset and/or progression of bone degeneration. Similarly, Selective Estrogen Receptor Modulators (SERM's), such as raloxefine, may be used to simulate increased estrogen in the body and thus slow bone loss. Calcitonin may be prescribed and is a material that is naturally produced by cells in the thyroid gland. Calcitonin acts directly on osteoclasts (via receptors on the cell surface for calcitonin) to modify the osteoclasts and thus stop bone resorption. Bisphosphonates, such as etidronate (DIDRONEL®), pamidronate (AREDIA®), alendronate (FOSAMAX®), risedronate (ACTONEL®), zoledronate (ZOMETA® or RECLAST®), and ibandronate (BONIVA®), can increase bone strength through increased mineralization density and decrease bone resorption. The bisphosphonates are all related to pyrophosphate, which is a byproduct of cellular metabolism and is a natural circulating inhibitor of mineralization in the blood and urine. Although pyrophosphates cannot enter bones (i.e., because the cell lining destroys pyrophosphate with alkaline phosphatase), bisphosphonates can enter the bone (and attach very strongly) due to chemical substitution in the compounds. Although such drugs may provide some level of usefulness, recent studies have suggested that long-term use of bisphosphonates can increase the risk of spontaneous subtrochanteric and femoral shaft fractures (i.e., atypical fractures). Denosumab (PROLIA®) is another pharmaceutical that was recently approved by the U.S. Food and Drug Administration for twice-a-year injections in osteoporotic patients with high fracture risk or patients that cannot tolerate other treatments. Denosumab is a fully human, monoclonal antibody that binds the RANK ligand and alters the body's natural bone remodeling process. Although long-term effects of the use of this antibody are not yet known, doctors have been warned to monitor patients for adverse reactions, such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Further, since the antibody alters the body's immune system, there has been evidence that use of the antibody can increase risk of serious infection in the patient. Yet another treatment, teriparatide (FORTEO®), is a recombinant parathyroid hormone (rPTH) that has the paradoxical effect of increasing bone mass by altering the pattern of exposure to the body's natural parathyroid hormone (PTH) and thus altering the skeletal effect of chronic PTH elevation, which can result in increased bone breakdown, a loss of calcium, and osteoporosis. Through activation of various bone metabolic pathways, the rPTH increases the number of active osteoblasts, decreases the naturally programmed death of osteoblast cells, and recruits bone-lining cells as osteoblasts. The drug appears to act largely upon the bone-building osteoblast cells and stimulating them to over activity. Safety studies in rats indicated a possibly increased risk of osteosarcoma associated with use of rPTH. Thus, there remains a need in the art for treatments that do not require long-term medication use with possible effects that, although unintended, may still be harmful.
Non-pharmaceutical treatments typically are used only after a fracture occurs. For example, fractures (particularly vertebral) may be treated by instant fixation wherein poly(methyl methacrylate) cement (typically referred to as “bone cement”) or a similar non-resorbable material, is inserted into the fracture to permanently harden and “fix” the bone in place. Although such treatments can attend to the presenting fracture, the unnatural physical properties (i.e., hardness, modulus, etc.) of the bone after the treatment are believed to increase the possibility of fracture of adjacent bone, particularly where the adjacent bone is in an advanced state of osteoporosis. Moreover, such treatments do not result in formation of natural bone in the fracture but rather function as non-resorbable bone replacements.
Despite the presence of pharmaceutical and surgical treatments for bone degeneration and fracture, there remains a need in the art for further treatments that can increase BMD in key areas to reduce risk of fractures and concomitant health risks, including death. Particularly, it would be useful to have means for treatments that target specific areas of the skeleton at high fracture risk by actually forming new, healthy (i.e., normal) bone material. Such treatments would not be subject to the current limitations of the art.